It is generally recognized that the development of dental plaque begins with the adhesion of bacteria to the teeth. Bacterial adhesion to tooth surfaces usually involves stereospecific interactions between cell surface binding proteins, referred to as adhesins, and cognate structures which form binding sites either in salivary pellicle, or on the surfaces of other bacteria resident in plaque, or in the extracellular plaque matrix (Gibbons, R. J.; J Dent Res 68,750-760).
Many of the oral bacterial adhesins described in the art exhibit carbohydrate-specific binding and are often found on filamentous extensions (i.e., pili or fimbriae) which protrude from cell surfaces. These carbohydrate recognition structures, which are also referred to as lectins, mediate binding to host-derived or microbial-derived saccharide-containing structures on the teeth. Several different bacterial lectins have been described in the literature. Fucose-specific lectins have been described for several oral bacterial species, including those belonging to the genera Actinomyces, Capnocytophaga, and Streptococcus. Rhamnose-specific lectins have been isolated from oral species including Capnocytophaga sp.
By far, the lectins most commonly expressed by plaque bacteria are .beta.-galactoside-specific or "lactose sensitive" adhesins. The genera of bacteria which produce .beta.-galactoside-specific adhesins cover a diverse taxonomic range, including Actinomyces, Streptococcus, Porphyromonas, Fusobacterium, Haemophilus, Capnocytophaga, Veillonella, Prevotella, Staphylococcus, and Neisseria; these represent both primary and secondary colonizers of the teeth (Kollenbrander, P. E.; Crit Rev Microbiol 17:137-159). Kollenbrander notes that bacterial coaggregation plays an active role in formation of dental plaque and adherence of bacteria to epithelial cells in the oral econiche.
Most attempts to control plaque through anti-adhesion mechanisms have involved non-stereospecific inhibition of bacterial attachment to the teeth, usually with compositions containing surface-active polymers. For instance, G. B. Pat. No. 2,224,204A and U.S. Pat. No. 4,877,603 disclose oral compositions which include phosphonate-containing polymers that inhibit bacterial attachment to hydroxyapatite surfaces. Similarly, U.S. Pat. No. 4,663,202 discloses a method for treating surfaces with combinations of polymers which form barriers that retard bacterial adsorption.
With respect to blocking stereospecific interactions which mediate oral bacterial adherence, the use of mono- and oligosaccharides has been described, as inhibitors of lectin-mediated adhesion to human cells. For instance, abstract of U.S. Pat. No. 7,349,772 describes oligosaccharides isolated from S. sanguis which inhibit the build-up of adhesive dental plaque. Gaffar et al. (U.S. Pat. No. 5,002,759) disclose oligosaccharides containing either a galactose moiety (which may be .beta.-galactose) and/or a fucose moiety as agents in dentifrice preparations for inhibiting adherence of Streptococcus pyogenes to human epithelial cells. European Patent Application 184,121 discloses the use of galactose and/or lactose as anti-caries agents in foods, drinks, and pharmaceutical preparations. Neeser (U.S. Pat. Nos. 4,992,420 and 4,994,441) describes kappa-caseino-glycopeptide compounds and desialylated derivatives thereof (the derivatives contain .beta.-galactose groups) as inhibitors of in vitro adhesion by dental plaque bacteria to human erythrocytes.
Lynch et al. (U.S. Pat. No. 4,855,128) disclose polysaccharides such as xanthan gum, gum tragacanth, guar gum, gum karaya, chondroitin sulfate, polygalacturonic acid, (pectin) sodium alginate and carrageenans of the kappa/lambda configuration as plaque-inhibitory agents which inhibit bacterial coaggregation; carrageenans of kappa/lambda configuration and chondroitin sulfate contain .beta.-galactose.
Stromberg et al. (J. Biol. Chem. 265,11251-11258) disclose that N-acetyl-galactosamine-.beta.1,3-galactose-O-ethyl is an inhibitor of binding by Actinomyces viscosus and Actinomyces naeslundii to human erythrocytes. McIntire et al. (Infection and Immunity, vol. 41, No. 2, 848-850) have described O-glycosides of galactose-.beta.1,3-N-acetyl-galactosamine, including phenyl, phenylethyl, and nitrophenyl derivatives, which inhibit coaggregation between Actinomyces sp. and Streptococuus sanguis; McIntire et al. note that the addition of aglycones increased the inhibitory activity significantly but not greatly.
Stromberg et al. ("Synthetic Receptoranalogues Prevent Plaque Formation in Man", Abstracts of International Association for Dental Research Scandinavian Division, Helsinki, Aug. 22-24, 1991) disclose a study demonstrating the plaque inhibitory activity of GalNAc.beta.-3Gal.alpha.1-O-ethyl, which blocked adherence of Actinomyces strains 12104 and LY7. Clinical plaque strains were evaluated in a mouth rinse experiment including five human individuals. The study is said to demonstrate that receptor analogues such as GalNAc.beta.-3Gal.alpha.1-O-ethyl, may prove useful in future antiplaque therapy. O-glycosides described by Stromberg and McIntire are structurally different from glycosylamines included in applicants' invention. In the latter compounds, nitrogen is connected to carbon number 1, whereas in the O-glycosides described by Stromberg and McIntire nitrogen is connected to carbon number 2. Further, O-glycosides described by the Stromberg and McIntire references are expensive molecules and their synthesis is complicated; hence, their practical utility is limited to the study of the stereospecificity of bacterial binding. By contrast, glycosylamines included in the present invention are relatively inexpensive and synthetically versatile.
As to non-dental art, abstracts of Japanese Patent Applications 03112905 and 03112904 disclose the use, as antibacterials for preserving food and cosmetics, of 2-acetylamino-N-alkyl-glycosylamines and alkyl-glycosyl-amines, particularly glucosamines represented by structures 1 and 2, respectively. ##STR1##
The Japanese disclosures are not aimed at delivering antiplaque or antiadhesion benefits or at affecting oral indigenous bacteria or at targeting .beta.-galactoside specific binding proteins on oral bacteria. None of the bacteria listed in the Japanese patents are involved in dental plaque formation.
Rosenberg et al. (Infection and Immunity, March 1983, 1024-1028) disclose that emulsan, which consists of D-galactosamine (anomeric structure not reported) containing polysaccharide backbone with covalently linked fatty acid chains, prevents adherence of A. calacoaceticus and S. pyogenes to buccal epithelial cells and is highly effective in removing bound indigenous bacteria. Emulsan is a polyanionic heteropolysaccharide with a molecular weight average of 9.9.times.10.sup.5 Like in the Stromberg and McIntire compounds discussed above, in the galactosamine units of emulsan nitrogen is connected carbon number 2 as opposed to the present compounds where the linkage is at carbon number 1. Eigen et al. (U.S. Pat. No. 4,737,359) disclose toothpaste or mouthwash preparations containing emulsan. Emulsan is said to reduce plaque formation by inhibiting attachment of S. mutans, which is said to be due to the presence of a galactosamine-specific lectin on the surface of S. mutans. Eigen et al. note the possibility that emulsan acts by breaking the bacterial lectin-carbohydrate interactions.
While emulsan may be an effective plaque inhibitor, emulsan must be produced by biotechnological procedures, i.e. through fermentation procedures which require extensive downstream processing and purification and which are relatively expensive. Since the production of emulsan is dependent on bacteria, emulsan cannot be easily modified (modification requires post-synthetic chemical treatment). Therefore, the use of material which can be produced and modified by synthetic procedures which are relatively less complex and less expensive than the biotechnological procedures involved in production of emulsan, would be desirable.
Accordingly, it is an object of the present invention to provide oral hygiene compositions which include specific N-containing derivatives of saccharides which include at least one .beta.-D-galactose group, or .beta.-D-N-acetyl galactosamine group, or .beta.-D-fucose group, or L-rhamnose group as antiplaque agents.
It is another object of the present invention to provide oral hygiene compositions which contain effective yet commercially feasible antiplaque amino sugars.
It is another object of the invention to provide oral hygiene compositions which include antiplaque agents which can be produced and modified by synthetic procedures.
It is still another object of the invention to provide methods of inhibiting bacterial adhesion and/or bacterial growth in the oral cavity.
These and other objects of the invention will become more apparent from the detailed description and examples that follow.